Herpes simplex labialis (also referred to as herpes labialis, cold sore, fever blister, recurrent herpes labialis, or orolabial herpes) is an infection on epithelial cells of the oral mucosal epithelium (generally including the lip). Herpes labialis infection takes place when the herpes simplex virus comes into contact with oral mucosal tissue or abraded skin of the mouth. An outbreak typically causes small painful blisters or sores on or around the mouth, usually along with fever, headache, or body aches. The sores typically heal within 2-3 weeks, but the herpes virus remains dormant in the facial nerves, following orofacial infection. Viral reactivation may be triggered by stressors such as UV light, fever, psychological stress, or local tissue trauma. In symptomatic patients, the virus is periodically reactivated to create sores in the same area of the mouth or face affected by the original infection. Rare reinfections occur inside the mouth (intraoral HSV stomatitis) affecting the gums, alveolar ridge, hard palate, and the back of the tongue, possibly accompanied by herpes labialis. In asymptomatic patients, viral shedding may still take place.
Infection by the type 1 strain of herpes simplex virus (HSV-1) is most common in herpes simplex labialis, with HSV-2 strain implicated in 10-15% of oral infections. Once the virus has entered the body, it moves from the mouth to the central nervous system, where it remains latent. In approximately one-third of people, the virus can reactivate to cause disease. When reactivation occurs, the virus travels down the nerves to the skin, where it may cause blisters (cold sores) around the lips, in the mouth or, in about 10% of cases, on the nose, chin, or 1777726.2 cheeks. Cold sore outbreaks may be influenced by stress, menstruation, sunlight, sunburn, fever, dehydration, or local skin trauma. Surgical procedures such as dental or neural surgery, lip tattooing, or dermabrasion are also common triggers.
Herpes esophagitis is a viral infection of the esophagus caused by HSV. While the disease most often occurs in immunocompromised patients (including post-chemotherapy, immunosuppression with organ transplants and in AIDS), herpes esophagitis can also occur in immunocompetent individuals. Patients experience odynophagia (painful swallowing) and dysphagia. Other symptoms can include food impaction, hiccups, weight loss, fever, and on rare occasions upper gastrointestinal bleeding and tracheoesophageal fistula.
The discovery of acyclovir revolutionized the way HSV-1 is treated, and the commonly administered drugs to treat herpes labialis and herpes esophagitis (such as famciclovir and valacyclovir) are derived from this compound. Such drugs are highly effective at treating HSV-1 maladies. However, relying on drugs that share a common mechanism of action introduces a major risk of drug resistance. Drug resistant strains of HSV-1 exist predominantly in the immunocompromised population, because the immune system normally promotes HSV-1 latency in the trigeminal ganglion and is instrumental in clearing the epithelial disease. For the roughly 5% of HIV-positive patients and 4-10% of stem cell recipients that harbor drug resistant HSV-1 strains, the only therapeutic options for treating HSV-1 are highly toxic and not nearly effective as acyclovir compounds. Two main resistance mechanisms to acyclovir-like compounds are known: at the thymidine kinase (TK) stage and at the DNA polymerase stage. Resistance through mutation of the TK gene is seen for drugs that require activation by the viral TK (e.g., acyclovir, ganciclovir, idoxuridine), but some resistant DNA polymerase mutants have also been reported. Cross-resistance between nucleoside analogue drugs further complicates the problem, highlighting the need for development of novel antiviral therapies.
HSV-1 interacts with host molecular machinery to optimize various aspects of the cellular environment for its own replication. The virus controls fundamental cellular functions, such as transcription, translation, cell cycle, autophagy, apoptosis, nuclear architecture, and antigen presentation. Among the host pathways hijacked by HSV-1 is the DNA damage response (DDR), which is a complex network of proteins responsible for the maintenance of genomic integrity of the cell. Sensor proteins of the DDR respond to DNA lesions and promote their repair by facilitating the assembly of repair proteins at the damaged DNA loci. Simultaneously, the DDR induces temporary cell cycle arrest to prevent the lesion from being passed on to the daughter cells. The DDR also induces transcriptional changes to optimize the cellular response to the incurred lesion. In the case of overwhelming or irreparable damage, the DDR promotes apoptosis of the affected cell. Three main sensor kinases serve as the apical proteins in the DDR: ATM (ataxia telangiectasia mutated), ATR (ataxia telangiectasia and Rad3 related), and DNA-PK (DNA-dependent protein kinase).
There is a need in the art for improved compositions and methods for the treatment of herpes simplex labialis. There is a further need in the art for improved compositions and methods for the treatment of herpes esophagitis. The present invention satisfies these unmet needs.